This invention relates generally to a bioabsorbable implantable endoprosthesis having one or more reservoir portions including hollow, cavity, or porous portions to accumulate by-products of degradation.
Self-expanding medical prostheses frequently referred to as stents are well known and commercially available. They are, for example, disclosed generally in the Wallsten U.S. Pat. No. 4,655,771, the Wallsten et al. U.S. Pat. No. 5,061,275 and in Hachtmann et al., U.S. Pat. No. 5,645,559. Devices are used within body vessels of humans for a variety of medical applications. Examples include intravascular stents for treating stenoses, stents for maintaining openings in the urinary, biliary, tracheobronchial, esophageal, and renal tracts, and vena cava filters.
A delivery device which retains the stent in its compressed state is used to deliver the stent to a treatment site through vessels in the body. The flexible nature and reduced radius of the compressed stent enables it to be delivered through relatively small and curved vessels. In percutaneous transluminal angioplasty, an implantable endoprosthesis is introduced through a small percutaneous puncture site, airway, or port and is passed through various body vessels to the treatment site. After the stent is positioned at the treatment site, the delivery device is actuated to release the stent, thereby allowing the stent to self-expand within the body vessel. The delivery device is then detached from the stent and removed from the patent The stent remains in the vessel at the treatment site as an implant.
Stents must exhibit a relatively high degree of biocompatibility since they are implanted in the body. An endoprosthesis may be delivered into a body lumen on or within a surgical delivery system such as preferred delivery devices shown in U.S. Pat. Nos. 4,954,126 and 5,026,377. Suitable materials for use in such delivery devices are described in U.S. patent application Ser. No. 08/833,639, filed Apr. 8, 1997. The stents of the present invention may be delivered by alternative methods or by using alternative devices.
Commonly used materials for known stent filaments include Elgiloy(copyright) and Phynox(copyright) metal spring alloys. Other metallic materials than can be used for self-expanding stent filaments are 316 stainless steel, MP35N alloy, and superelastic Nitinol nickel-titanium. Another self-expanding stent, available from Schneider (USA) Inc. of Minneapolis, Minn., has a radiopaque clad composite structure such as shown in U.S. Pat. No. 5,630,840 to Mayer. Self-expanding stents can be made of a Titanium Alloy as described in U.S. patent application Ser. No. 08/598,751, filed Feb. 8, 1996.
The strength and modulus of elasticity of the filaments forming the stents are also important characteristics. Elgiloy(copyright), Phynox(copyright), MP35N and stainless steel are all high strength and high modulus metals. Nitinol has relatively lower strength and modulus.
The implantation of an intraluminal stent will preferably cause a generally reduced amount of acute and chronic trauma to the luminal wall while performing its function. A stent that applies a gentle radial force against the wall and that is compliant and flexible with lumen movements is preferred for use in diseased, weakened, or brittle lumens. The stent will preferably be capable of withstanding radially occlusive pressure from tumors, plaque, and luminal recoil and remodeling.
There remains a continuing need for self-expanding stents with particular characteristics for use in various medical indications. Stents are needed for implantation in an ever growing list of vessels in the body. Different physiological environments are encountered and it is recognized that there is no universally acceptable set of stent characteristics. The strength and modulus of elasticity of the filaments forming the stents are important characteristics.
A need exists for a stent which has self expanding characteristics, but which is bioabsorbable. A surgical implant such as a stent endoprosthesis must be made of a non-toxic, biocompatible material in order to minimize the foreign-body response of the host tissue. The implant must also have sufficient structural strength, biostability, size, and durability to withstand the conditions and confinement in a body lumen.
All documents cited herein, including the foregoing, are incorporated herein by reference in their entireties for all purposes.
The present invention is an improved implantable medical device comprised of a tubular, radially compressible, axially flexible and radially self-expandable structure including elongate filaments having reservoir portion. The filaments are formed in a braid-like configuration. The filaments consist of a bioabsorbable polymer which exhibits a relatively high degree of biocompatibility.
Briefly, self-expanding stents of the present invention are formed from a number of resilient filaments which are helically wound and interwoven in a braided configuration. The stents assume a substantially tubular form in their unloaded or expanded state when they are not subjected to external forces. When subjected to inwardly directed radial forces the stents are forced into a reduced-radius and extended-length loaded or compressed state. The stents are generally characterized by a longitudinal shortening upon radial expansion.
In one preferred embodiment, the device is a stent which substantially consists of a plurality of elongate polylactide bioabsorbable polymer filaments, helically wound and interwoven in a braided configuration to form a tube.
There is a need for a bioabsorbable implantable endoprosthesis that has a high rate of degradation and may be tailored to degrade over predetermined periods of time. One way to avoid long-term complications from an implant is to make the implant bioabsorbable so that the device is naturally eliminated from the treatment site after it has served its intended function.
Such a bioabsorbable implantable endoprosthesis would be especially advantageous for medical procedures requiring an endoprosthesis for short term or temporary use. For example, it would be advantageous to implant an implantable endoprosthesis that functions for a specific period of time and does not require a surgical procedure for removal at the end of its functional lifetime. With such an endoprosthesis, there is no need to remove the endoprosthesis because the bioabsorbable material therein decomposes over a period of time into non-toxic biological substances (e.g. lactic acid and glycolic acid) which are easily metabolized or excreted by the body. Such a bioabsorbable implantable endoprosthesis would be advantageous in urological, biliary, vascular, and airway applications where use is desired for only weeks, months, or a few years while a benign stricture is cured or healed, or for use in pre-operative palliation. Such a device may also offer an advantage in that shorter resorption times may reduce the time of inflammatory response and may reduce scarring.
Bioabsorbable implantable endoprostheses of the present invention include stents, stent-grafts, grafts, filters, occlusive devices, and valves which may be made of poly(alpha-hydroxy acid) such as polylactide [poly-L-lactide (PLLA), poly-D-lactide (PDLA)], polyglycolide (PGA), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, poly(hydroxybutyrate), polyanhydride, polyphosphoester, poly(amino acids), or related copolymers materials, each of which have a characteristic degradation rate in the body. For example, PGA and polydioxanone are relatively fast-bioabsorbing materials (weeks to months) and PLA and polycaprolactone are relatively slow-bioabsorbing material (months to years).
An implantable endoprosthesis constructed of a bioabsorbable polymer provides certain advantages relative to metal stents such as natural decomposition into non-toxic chemical species over a period of time. Also, bioabsorbable polymeric stents may be manufactured at relatively low manufacturing costs since vacuum heat treatment and chemical cleaning commonly used in metal stent manufacturing are not required.
An implantable endoprosthesis made of substantially solid elongate members consisting of PLA generally will require 1-3 years to absorb in a body. However, an implantable endoprosthesis made of PLA, having comparatively shorter resorption times than 1-3 years is desirable for certain indications such as pediatric endoluminal interventions where anatomical growth rates are high and implant size revisions are often necessary. The endoprosthesis of the present invention would be advantageous because the endoprosthesis would absorb over a relatively shorter time and removal thereof would be unnecessary. As the child grows, the appropriate size implantable endoprosthesis could be placed in the body when needed. The resorption time for an implantable endoprosthesis made of a poly (alpha-hydroxy acid) polymer having elongate members including hollow, cavity, or porous portions may be reduced to several days or a few weeks for PGA or to several months to years for PLA.
The period of time that a bioabsorbable implantable endoprosthesis is functional is dependent upon the degradation rate of the bioabsorbable material and the environment into which it is implanted. The degradation rate of a bioabsorbable endoprosthesis is dependent on chemical composition, processing methods, dimensions, sterilization methods, and geometry of the reservoir portions (i.e. hollow, cavity, or porous portions) of the present invention.
Bioabsorbable polymer stents are radiolucent and the mechanical properties of the polymers are generally lower than structural metal alloys. Bioabsorbable stents may require radiopaque markers and may have a larger profile on a delivery catheter and in a body lumen to compensate for the lower material properties.
Bioabsorbable PLLA and PGA material are degraded in vivo through hydrolytic chain scission to lactic acid and glycolic acid, respectively, which in turn is converted to CO2 and then eliminated from the body by respiration. Heterogeneous degradation of semicrystalline polymers occurs due to the fact that such materials have amorphous and crystalline regions. Degradation occurs more rapidly at amorphous regions than at crystalline regions. This results in the product decreasing in strength faster than it decreases in mass. Totally amorphous, cross-linked polyesters show a more linear decrease in strength with mass over time as compared to a material with crystalline and amorphous regions. Degradation time may be affected by variations in chemical composition and polymer chain structures, and material processing.
PLA monofilaments may be produced by a process involving seven general steps as summarized herein. First, a polymer formed of poly-L-lactic acid is brought to an elevated temperature above the melting point, preferably 210xc2x0-230xc2x0 C. Second, the material is then extruded at the elevated temperature into a continuous fiber, by a conventional process, at a rate of from about three to four feet per minute. Third, the continuous fiber is then cooled to cause nucleation. The cooling is preferably performed by passing the fiber through a nucleation bath of water. Fourth, the material then passes through a first puller, which runs at about the same speed as the extruder, and places the material under slight tension. Fifth, the fiber is then heated to a temperature between about 60xc2x0 C. and about 90xc2x0 C. (preferably 70xc2x0 C.) as it passes through a heated oven. To perform annealing, the oven can be designed to be quite long and heated near the end, so that the orientation and annealing take place in the same oven. Alternatively, a separate oven can be placed directly after the orientation oven. The annealing step heats the fibers to a range of about 65xc2x0 C. to about 90xc2x0 C., preferably closer to 90xc2x0 C. Sixth, while being heated in the orientation oven and the annealing oven, the fiber is drawn between the first puller located before the orientation oven and a second puller located after the annealing oven (if a separate oven). The material is drawn at a draw ratio of between about 5 to about 9, preferably between about 6 and about 8. Draw ratio describes either the reduction in diameter or the extension in length resulting from polymer extrusion or drawing. Quantitatively, the drawing ratio is a unitless value equal to the extruded or drawn length divided by the original length. Maintaining tension through the annealing step prevents shrinkage in later use. The second puller, located at the exit of the oven, runs at an increased speed necessary to provide the desired draw ratio. As the fiber exits the oven and passes through the second puller the tension is immediately released before the material cools. Seventh, finally, the fiber is collected onto spools of desired lengths.
Strength of the filaments generally increases with draw ratio and with lower draw temperatures. A draw ratio of between 5 and 9 is preferred. PLA is generally amorphous because of the material""s slow crystallization kinetics. Very slow cooling after drawing of the filament or use of a nucleating agent will cause crystallization. However, the material may be annealed at temperatures above about 60xc2x0 C. to cause crystallization, and generally, the strength decreases slightly and the modulus increases. Annealing is preferably performed after drawing to release residual stresses and to homogenize the surface to center variations in structure. Annealing will preferably be performed at a temperature of between about 60xc2x0 C. and 150xc2x0 C. for a period of time between about 5 and 120 minutes.
An endoprosthesis with hollow filaments and closed filament ends can be made by braiding individual strands of extruded tubing. The polymer is melt-extruded through a die containing a center mandrel such that the product is a hollow tube strand. The tube strands are collected onto spools and in a separate operation are transferred from the spools to braid bobbins. After braiding the tubular strands the braid is transferred from the braid mandrel to an anneal mandrel and annealed at a temperature between the glass transistion temperature and the melt temperature of the polymer. The annealed stents are slid off of the anneal mandrel and are cut to the desired endoprosthesis length by clipping each strand in the stent with wire cutters. As the cutting surfaces of the wire cutters close upon the strand the polymer is crimped or flowed and the hollow center is thereby closed. The tubular strands are closed at each end of the stent as a result of the strand cutting operation and the hollow portions are thus generally sealed to prevent significant drainage of accumulating polymer degradation products. It is not necessary for the ends of the hollow strands in a stent to always be sealed closed since capillary forces that would draw the degradation products toward any open ends or that would draw in bodily fluids would not act over such long lengths as with a helical interbraided strand in a stent.
Reference is made to Enhancement of the Mechanical properties of polylactides by solid-state extrusion, W. Weiler and S. Gogolewski, Biomaterials 1996, Vol. 17 No. 5, pp. 529-535; and Deformation Characteristics of a Bioabsorbable Intravascular Stent, Investigative Radiology, December 1992, C. Mauli, Agrawal, Ph.D., P.E., H. G. Clark, Ph.D., pp. 1020-1024.
Mechanical properties generally increase with increasing molecular weight. For instance, the strength and modulus of PLA generally increase with increasing molecular weight. Degradation time generally decreases with decreasing initial molecular weight (i.e., a stent made of a low molecular weight polymer would be bioabsorbed before a stent made of a high molecular weight polymer). Low molecular weight PLA is generally more susceptible to thermo-oxidative degradation than high molecular weight grades, so an optimum molecular weight range should be selected to balance properties, degradation time, and stability. The molecular weight and mechanical properties of the material generally decrease as degradation progresses. PLA generally has a degradation time greater than 1 year. Ethylene oxide sterilization process (EtO) is a preferred method of sterilization. PLA has a glass transition temperature of about 60xc2x0 C., so care must be taken not to store products in environments where high temperature exposure greater than 60xc2x0 C. may result in dimensional distortion.
PLA, PLLA, PDLA and PGA include tensile strengths of from about 40 thousands of pounds per square inch (ksi) to about 120 ksi; a tensile strength of 80 ksi is typical; and a preferred tensile strength of from about 60 ksi to about 120 ksi. Polydioxanone, polycaprolactone, and polygluconate include tensile strengths of from about 15 ksi to about 60 ksi; a tensile strength of about 35 ksi is typical; and a preferred tensile strength of from about 25 ksi to about 45 ksi.
PLA, PLLA, PDLA and PGA include tensile modulus of from about 400,000 pounds per square inch (psi) to about 2,000,000 psi; a tensile modulus of 900,000 psi is typical; and a preferred tensile modulus of from about 700,000 psi to about 1,200,000 psi. Polydioxanone, polycaprolactone, and polygluconate include tensile modulus of from about 200,000 psi to about 700,000 psi; a tensile modulus of 450,000 psi is typical; and a preferred tensile modulus of from about 350,000 psi to about 550,000 psi.
PLLA filament has a much lower-tensile strength and tensile modulus than, for example, Elgiloy(copyright) metal alloy wire which may be used to make braided stents. The tensile strength of PLLA is about 22% of the tensile strength of Elgiloy(copyright). The tensile modulus of PLLA is about 3% of the tensile modulus of Elgiloy(copyright). Stent mechanical properties and self-expansion are directly proportional to tensile modulus of the material. As a result, a PLLA filament braided stent made to the same design as the metal stent has low mechanical properties and would not be functional. The polymeric braided stents should have radial strength similar to metal stents and should have the required mechanical properties capable of bracing open endoluminal strictures.
The term xe2x80x9csubstantially degradesxe2x80x9d means that the stent has lost at least 50% of its structural strength. It is preferable that the stent lose about 100% of its structural strength. The included angle between interbraided filaments in the axial orientation is termed xe2x80x9cbraid anglexe2x80x9d prior to annealing and is termed xe2x80x9cfilament crossing anglexe2x80x9d after annealing. A braid becomes a stent after annealing.
Bioabsorbable resins such as PLLA, PDLA, PGA and other bioabsorbable polymers are commercially available from several sources including PURAC America, Inc. of Lincolnshire, Ill.
In sum, the invention relates to a bioabsorbable implantable endoprosthesis comprising a tubular, radially compressible, axially flexible, and radially self-expandable braided and annealed structure having a diameter in a free state, the structure including from about 10 to about 36 filaments including poly (alpha-hydroxy acid), the structure having a radial force of from about 40 grams to about 300 grams at about one-half diameter, each filament having a tensile strength of from about 20 ksi to about 120 ksi, and a tensile modulus of from about 400,000 psi to about 2,000,000 psi, and an average diameter of from about 0.15 mm to about 0.6 mm, the filaments having a crossing angle of from about 120 degrees to about 150 degrees in a free state, each filament including one or more reservoir portions with an average cross-sectional area greater than about 7.9xc3x9710xe2x88x927 mm2 and in each filament, the sum of the one or more reservoir portions when empty represents a total volume percentage greater than about 5% of the total filament volume. The bioabsorbable implantable endoprosthesis of claim 1 wherein the sum of the one or more reservoir portions when empty represents a total volume percentage of from about 20% to about 40%. The degradation by-products may at least partially collect in the reservoir portions. The degradation by-products in the reservoir portions may have an average pH level which decreases over time in vivo. The reservoir portions may be hollow, cavity, porous, or combinations thereof. The average pH level in the reservoir may be between about 3 and 7. The endoprosthesis may substantially degrades in vivo in less than 3 years. The endoprosthesis may provide structural integrity to a body lumen for less than 2 years. The filaments may be mono-filament, multi-filament, ribbon, suture, thread, fiber, or combinations thereof. The implantable endoprosthesis may be a stent, stent-graft, graft, filter, occlusive device, or valve. The filaments may gain weight in vivo in an amount of from about 0.1% to about 20% of initial mass prior to losing weight in an amount of from about 0.1% to about 70% of initial mass prior to disintegration. The reservoir portions may accumulate the degradation by-product for a predetermined amount of time. The filaments may comprise PLLA, PDLA, or combinations thereof and substantially degrade in vivo in from about 1 year to about 2 years. The filaments may comprise polylactide, polyglycolide, or combinations thereof and substantially degrade in vivo in from about 3 months to about 1 year. The filaments may comprise polyglycolide, polygluconate, polydioxanone, or combinations thereof and substantially degrade in vivo in from about 1 week to about 3 months. The thickness of the filament t, in mm, may be equal to about (D/(1.8D+15))xc2x10.03 mm, where D, in mm, is the free state diameter. The number of filaments, N, may be equal to about (D/(0.022D+0.17))xc2x14 filaments, where D, in mm, is the free state diameter. The endoprosthesis may have at least one end of diminishing diameter. The filaments may have a tensile modulus of from about 700,000 to about 1,200,000 psi. The endoprosthesis may have a braid angle of from about 60 degrees to about 150 degrees when implanted in vivo. The filament may further comprises a water absorption diffusion distance of from about 1 micron to about 250 microns.
The invention also relates to a bioabsorbable implantable endoprosthesis comprising one or more elongate elements including poly (alpha-hydroxy acid), each filament including one or more reservoir portions with an average cross-sectional area greater than about 7.9xc3x9710xe2x88x927 mm2, and in each filament, the sum of the one or more reservoir portion when empty represents a total volume % greater than about 10% wherein the poly (alpha-hydroxy acid) bioabsorbs and degradation by-products therefrom collect in the reservoir. The hollow portions when empty may represent a volume percentage of at least 5 percent, cavity portions when empty may represent a volume percentage of at least 5 percent, and porous portions when empty may represent a volume percentage of at least 10 percent.
The invention also relates to a method of using an implantable endoprosthesis including: disposing a implantable endoprosthesis made of poly (alpha-hydroxy acid) in a delivery system, the endoprosthesis comprising a tubular, and radially expandable structure made of elongate filaments including hollow, cavity, or porous portions. Each portion with an average cross-sectional area greater than about 7.9xc3x9710xe2x88x927 mm2 and the sum of the portions when empty represent a total volume % greater than about 10%; inserting the delivery system and endoprosthesis in a body lumen; deploying the endoprosthesis from the delivery system into the body lumen; and allowing the hollow, cavity, or porous portions to accumulate degradation by-product from the poly (alpha-hydroxy acid).
The invention also relates to a method of manufacturing an implantable endoprosthesis comprising the steps: disposing a braided bioabsorbable polymer endoprosthesis on an annealing mandrel, the endoprosthesis comprising a tubular, and radially expandable structure made of elongate elements. The elongate elements including at least one hollow, cavity, or porous portion. Each portion with an average cross-sectional area greater than about 7.9xc3x9710xe2x88x927 mm2 and the sum of the portions when empty have a total volume % greater than about 10%; axially compressing the endoprosthesis; annealing the endoprosthesis at a temperature less than the melting point of the endoprosthesis for a time of from about 5 minutes to about 90 minutes; and cooling the endoprosthesis. The annealing temperature may be from about 130xc2x0 C. to about 160xc2x0 C. and the annealing time is from about 10 minutes to about 20 minutes. The method may further comprise the step of cutting the endoprosthesis into predetermined lengths. The method may further comprise a step of braiding the endoprosthesis on a braiding mandrel at a braid angle of from about 90 degrees to about 150 degrees. The method while annealing, the endoprosthesis has a braid angle of from about 130 degrees to about 150 degrees.
The invention also relates to a bioabsorbable endoprosthesis including at least one elongate element having an outer surface and a thickness. The element consisting of a bioabsorbable polymer which readily degrades in vivo. The element including one or more pores in diameter of from about 1 micron to about 20 microns. The pores when empty represent a volume percentage of from about 10% to about 50%. The pores accumulate by-product from the degradation of the bioabsorbable material.
The invention also relates to a bioabsorbable implantable endoprosthesis consisting essentially of a poly (alpha-hydroxy acid). The endoprosthesis prior to implantation having an outer surface containing a multitude of empty pores which open on the endoprosthesis outer surface and which have an average depth of at least about 0.5 micron. A sum of the pores have a total pore outer surface area at their outer openings on the outer surface of the endoprosthesis. The endoprosthesis has a total outer surface area which includes the total pore outer surface area, and the total pore outer surface area is from about 2 to about 40 percent of the total endoprosthesis surface area. The pores when empty may have an average cross-sectional area on the filament outer surface of at least about 7.9xc3x9710xe2x88x927 mm2. The pores when empty may have an average cross-sectional area on the filament outer surface of less than about 3.1xc3x9710xe2x88x924 mm. The pores when empty may have an average cross-sectional area on the filament outer surface of from about 7.9xc3x9710xe2x88x925 to about 1.8xc3x9710xe2x88x924 mm2.
The invention also relates to a bioabsorbable implantable endoprosthesis including at least one elongate element consisting essentially of poly (alpha-hydroxy acid). The element-and-having an outer surface. The elongate element prior to implantation containing at least one empty internal cavity which does not open to the element outer surface. The at least one cavity has an average cross-sectional area along a length of the element. The element has an average cross-sectional area along its length which includes the average cavity cross-sectional area, and the average cavity cross sectional area is from about 2 to about 40 percent of the average element cross-sectional area. The cavity when empty may have an average cross-sectional area of from about 10 to about 30 percent of the elongate element cross-sectional area.
The invention also relates to a bioabsorbable implantable stent having a tubular, radially compressible and self-expandable braided and annealed structure including a first set of-filaments each of which extends in a helix configuration along a center line of the stent and having a first common direction of winding; and a second set of filaments each of which extends in a helix configuration along a center line of the stent and having a second common direction of winding. The second set of filaments crossing the first set of filaments at an axially directed angle so as to form a plurality of interstices between filaments. A plurality of filaments have a length including PLLA, PDLA, PGA, or combinations thereof and having prior to implantation an empty lumen extending at least substantially through the entire length of the plurality of filaments. The plurality of filaments have further a tensile strength of from about 20 ksi to about 120 ksi, a tensile modulus of from about 400,000 psi to about 2,000,000 psi, and an average diameter of from about 0.15 mm to about 0.6 mm. The first set of filaments and second set of filaments act upon one another to create an outwardly directed radial force sufficient to implant the stent in a body vessel upon deployment from a delivery device. The second set of filaments may cross the first set of filaments at an axially directed angle of between about 120 and about 150 degrees when the stent is in a first free radially expanded state after being annealed but before being loaded on a delivery device. The stent may have a second free radially expanded state after being loaded and then released from a deployment device. The first and second sets of filaments may cross at an axially directed angle of between about 80 and 145 degrees when in the second free radially expanded state. The first and second sets of filaments may cross at an axially directed angle of between about 90 and 100 degrees when in the second free radially expanded state and the stent may have an outside diameter of between 3 and 6 mm when in the second free radially expanded state. The axially directed angle may be between about 110 and 120 when in the second free radially expanded state. The stent may have an outside diameter when in the second free radially expanded state and the stent may exert an outwardly directed radial force at one half of the outside diameter of from about 40 grams to about 300 grams. The stent may have an implanted state after being loaded, subsequently released from a deployment device, deployed into a body vessel, and then implanted in the body vessel, with the first and second sets of filaments crossing at an axially directed angle of between about 95 and 105 degrees when the stent is in the implanted state.
Still other objects and advantages of the present invention and methods of construction of the same will become readily apparent to those skilled in the art from the following detailed description, wherein only the preferred embodiments are shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments and methods of construction, and its several details are capable of modification in various obvious respects, all without departing from the invention. Accordingly, the drawing and description are to be regarded as illustrative in nature, and not as restrictive.